About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

January 31, 2013

Mipomersen Approved (Bonus Antisense Roundup Included)

Posted by Derek

So Isis and their partner Sanofi have received FDA approval for mipomersen (branded as Kynamro). Late last year, the European Medicines Agency turned them down, which has people wondering about the drug's future, but here they are, albeit with a warning on the label about liver toxicity.

Mipomersen is designed to lower the Apo-B lipoprotein in people with the most severe (homozygous) form of familial hypercholesterolemia. That's a small patient population, but they're definitely in need of help. The really significant thing about this approval, in my mind, is that it's a pure antisense therapy, and it comes about twenty years after there was supposed to be a world-changing flood of them. (Isis did get one through the process back in 1996, fomivirsen, but it's never had much of an impact). It was a standing joke back in the late 1980s/early 1990s that everyone had heard from a headhunter recruiting for one antisense company or another. (Sheesh, those were the days, eh? There still are search firms, right? When's the last time a headhunter rang your phone?)

I don't think that mipomersen will ever reach the heights that Isis thought it might a few years ago; the liver tox problems will see that it's only used in life-threatening situations. (I note that one time when I wrote about the drug, fans of ISIS showed up rolling their eyes at the mistaken notion that liver tox could ever be a problem). But I'm divided between congratulating them on finally getting something onto the market, and wondering about how difficult it's been to get there. As far as I know, the liver tox seen in this case is largely (completely?) thought to be due to the mechanism of action on lipid handling in the liver itself.

Actually, that lineup looks a lot like drug development in the rest of the industry, to be honest. Some stuff looks OK and is moving along, some not so OK, and some has wiped out. It's important to realize that even if liver tox is not some general feature of the mipomersen-generation antisense compounds, that we still have efficacy failures. Oh, that we do. The indications where we can really laser right in on a key target do not make a long list. Many of those are orphans, too. In contrast, the list of giant-unmet-medical-need indications where we can laser right in on a key target is, I think, waiting for something, anything, to be written on it.

I worked on antisense (we called them non-sense) compounds many years back. We were assured that they had to be non-toxic due to their binding only to one in a billion DNA sequences.

Well, someone forgot to tell the molecules that, because in at least some cases, using non-natural DNA oligomers, as we saw some horrible liver toxicity. I scaled up one DNA oligomer to 100's of mgs in 10 mg batches (that was a serious amount of work back then) for preclinical studies, as we were told that we would need to go very high before seeing any side effects, based on cellular tox. studies.

The first batch of mice died fairly quickly from liver tox. after about 10 mg each IV. Next batch got 5 mg, and they died aften a day or two from liver tox. The lowest dose was 1 mg each, which caused a slow dead from liver failure.

I can't go into details on the structures, they were modified DNA chains, but they were commonly claimed to be very non-toxic by some biotech. companies. I think that area has since been abandoned, but while I see some great potential in anti-sense DNA, especially for diagnostics and as tool compounds, I would not believe anyone who says that they are safe based on simple tests.

After all, most cells I have seen don't have livers or kidneys, so those tests are not very meaningful in that context. And I don't know why the compounds were liver toxic, we ran from that area very quickly and quietly.

For the sake of completeness, I think you should mention that another drug, lomitapide (Juxtapid), was recently approved (Dec 2012) for the same indication, albeit a different mechanism. And, it is an oral small molecule as opposed to an injected oligomer.

It's good to see both of the drugs becoming available to that population. It will be interesting to see how efficacy, side effect management, and pricing will be handled with two very different drugs in a relatively small population.

@3 and 7. I didn't even discuss details. I've been to China enough times to know I wouldn't leave a job here to go there, only if I had already eaten my savings, the shrubs in front of my house, and my car upholstery...

Does anyone know what happened to the antisense compound AEG 35156? I can't find any clues as to why the clinical trials were all terminated. It was a 19 mer, modified ends (4,11,4). Aegera was the company. Very cold trail.